Process for making enterically useful complex of spiramycin and product thereof



United States Patent ice 324L049 Patented Mar. 22, 1966 ability, (2) enteric release, or (3) sustained release. It 3,242,049 is possible, of course, to provide the complex with flavors PROCESS FOR MAKING ENTERICAL US or colors for aesthetic or identification purposes. If de- COMPLEX 0F SPIR MY N AND PRODUCT sired, suspensions of the complex material provided by THEREUF 5 the process may be made in suitable liquid or solid ve- Paul OBrien Dayton and Harry L. Roe In, Center-ville, p v

Ohio assinors to National Casi] Register hicles, and mixtures of the novel complexes may be made pany, Dayton, Ohio, a corporation of Maryland with other therapeutically necessary materials not neces- No Drawing. Filed May 20, 1963, S81. No. 281,768 Barfly m s d s to the p 2 Claims. 1, 167 5 The invention is deemed applicable to acid-base re- 10 actions between film-formers of physiological merit and This invention relates to a process for making a palatrnedicaments in general, to produce the desired reaction able enteric sustained-release medicament, and to its prodproduct. .uct, In practicing the process, it is best to use an excess Many medicines, which are unpalatable because of of the film-forming acid-reactant material in the reaction bitterness, must be given orally in a protective coating mixture, to insure complete reaction of the obnoxious so that they may be tolerated. If such medicines are medicament, the excess film-former in unreacted condito be released enterically in a sustained manner, there is ti n r maining as an innocuous residue which, if of sufiia three-fold problem to be solved; namely, cient :amourlilt, may itself be'of value in delaying enteric re ease of t e com ex b its mere h sical resence. (l) Palatability 2O p y p y p (2) Enteric release EXAMPLE I (3) Sustained release In this, the preferred example, acetone is used as a This invention has provided a process for treating ba-s-icsolveflt reactmg, room p ,reacting medioaments with acidqeacting physiobgicauy tu-re, sprramy-cm With cellulose acetate hydrogen phthalcompatible film-forming protective material, to form an acid-base complex that satisfies the three requirements Specifically splragnycm 15 best l as It l f without substantially interfering with the potency of the m w pubhcatlon The Merck Index Seventh edltlon, medicament component published by Merck Co., Inc., Rahway, New Jersey,

For the acid-reacting component there is used cellulose Umted States Amen'caa m 1960? to Wlta Page 972:

I U hth 1 te, a w u known and .SiOlOOL Spiramycin. Sequamycin; Selectomycin; Rovamycin; acetate hydroDenp 6 0, p P 5337 R.'P.; Provamycm; RP. 5337. C 60.7%. H cally acceptable enteric film formin protectivematerial. 9 07 N 3 7 O 7 1 For illustrating the basic-reactant component there is 2 (by ysls) used, as the preferred example, the antibiotic spiramycin, C22 2 H34 44NO7 g and as secPnd 'exafnple'there 13 used dextmmethorpha Antibiotic substance classified in the erythromycin-carboth obnoxiously bltter 1n taste and adapted for entenc 3 bomycin group and produced by Strepwmyces ambo use. faciens from soil of northern France: Co-sar, Ninet, Pin- In each example, the basicareactant medicament and the men, Preudhomme Rhngpoulenc], compt' rend acid-reactant protective material are brought together bioL 234, 149.8 (1952); Antibiotics Annual 19.54 1955 in liquid solution, in which they react to form a fine solid precipitate of particulate state This precipitate may 40 Amorphous base, slightly soluble in Waten Soluble be reduced in size 'so as to provide the desired release in most organic So1vents ]D20 80 ,(cwtl i mathtime-span in the intestinal tract, or tableted to achieve a 1 Adsopption 2311 lfmger Sustained release f P forming the P Sulfate, crystals, soluble in Water, methanol, ethanol, tlculate complex, the entire dissolution of each partlcle butanoL from the surface inwardly accounts for the release rate Active on Gram positive bacteria .rickettsiae' of the medicament component, which is not he Ca e in Cross resistance between microorganisms resistant to eryththe dissolution of a protective film coating of an entire romycin and carbomycin."

t bl t 01' in the case of the rupture of a coating corn- Cellulose acetate hydrogen phthalate has the structural prising a capsule wall for the entire dosage. The particle formula:

sizes of the complex particles going into a dose may be where n is chosen with a view to making a 15% soluselected so as to provide the desired release-rate of the tion of it, in acetone at room temperature (25 degrees material, the total surface area of the remaining particles centigrade :5 degrees), to have an approximate visof a dose giving the release rate at a given instant. 1t cosity of 50-90 centipoises, and to have an esterified is apparent that a dose may consist of particles of varph-thalyl content of 30%-40%, a free acid content of 6% ions predetermined sizes or of various reacted materials. maximum, and an esterified acetyl content of l7%22%,

While the invention finds its primary use in the menby weight. Specifically, one part of solution A is mixed tioned three respects, its utility may reside in any one with one part of Solution B at room temperature, and of the characteristics mentioned; that is to say, (1) palatthe reaction proceeds forthwith.

Solution A Grams Acetone 1897 Cellulose acetate hydrogen phthalate (as specified) 41 Solution B Acetone 788 Spiramycin (as specified) 41 The equal actual weights in grams of the combining materials are of no significance, as molecularly there is present an excess of the cellulose acetate hydrogen phthalate to assure complete reaction of the spiramycin. The yield was 73 grams of the complex as compared with a theoretical yield of 82 grams, or 89% of the calculated yield.

EXAMPLE II In this example, dextromethorphan is substituted for the spiramycin of Example I, in substantially the same weight proportions to provide the excess of the cellulose acetate hydrogen phthalate.

Dextromethorphan has the structure 011,0 and acts basically.

Comparable taste-masking, medicinal efiicacy, and yields were obtained as were obtained in Example I.

The concept of forming acid-base complexes in acetone solutions of cellulose acetate hydrogen phthalate and a basic-reactant material is applicable to all kinds of basereacting medicaments, be they orally repulsive or not, the enteric sustained release characteristics of the complexes being of importance in and of themselves apart from taste masking.

It is Within the concept of the invention to employ other acid-reacting film-forming enteric materials than the specified cellulose acetate hydrogen phthalate to react with spiramycin or dextromethorphan, and to employ dilferent kinds of reactant complexes combined in the same dosage, all to the end result specified.

The reaction may take place in other solvents than acetone, acetone having been specified as preferred as eminently suitable for pharmaceutical products. Other solvents and solvent systems that are suitable for use are listed in the following group:

Methyl ethyl ketone Diacetone alcohol Dioxane Methanokacetone 1:1 Methanolzacetone 3:1 Methanolzbenzene 1:1

Ethyl acetatezisopropanol 1 1 Furfuryl alcohol Furthermore, the indications are that mixtures of solvents Will work in the process; for instance, an acetone solution of cellulose acetate hydrogen phthalate will react with spiramycin dissolved in any one of the group of solvents named, with comparable yields.

EXAMPLE III This is the same as Example I except that the spiramycin is dissolved in 788 grams of methyl ethyl ketone instead of acetone to make Solution B, which is then mixed with Solution A.

EXAMPLE IV This is the same as Example II except that the dextrometh-orphan is mixed with dioxane.

EXAMPLE V This is the same as Example I except that double the amount of Solution A is used to form a great excess of cellulose acetate hydrogen phthalate in the final product to provide greater taste-masking and sustained release by bulking the complex with unreacted protective material. The amount of such excess is a matter of choice, up to four times as much providing a useful product.

EXAMPLE VI References Cited by the Examiner UNITED STATES PATENTS 2,866,735 12/1958 Himelick 167-82 3,000,785 9/1961 Ninet et al. 167-65 3,081,233 3/1963 Enz et al 167-82 3,121,043 2/1964 Tobin et al 16782 FOREIGN PATENTS 561,936 8/1958 Canada.

OTHER REFERENCES New and Nonofiicial Dru-gs, J. J. Lippincott, Philadelphia, Pa. (1961), p. 385.

JULIAN S. LEVITT, Primary Examiner.

FRANK CACCIAPAGLIA, JR., Examiner. 

1. THE ACID-BASE REACTION PRODUCT OF SPIRAMYCIN AND CELLULOSE ACETATE HYDROGEN PHTHALATE. 